DESCRIPTION: (Applicant's abstract) The long-term goal of the project is to determine how therapeutic drugs and toxins affect neuronal ion channels. The specific aims for the next 5 years of proposed funding concentrate on a pharmacological comparison of two sodium channel types in dorsal root ganglion (DRG) neurons: tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) channels. This focus was suggested in the review of the previous version of this application. Although TTX-S and TTX-R channels are also present in brain neurons, DRG cells were chosen as a model, since the proportion of TTX-R channels is generally small in brain, and the principal investigator already has substantial data on these channels in DRG. Whole-cell and single-channel patch clamp techniques will be used. Five specific aims are proposed, comparing the effects on TTX-S and TTX-R channels of divalent cations, natural toxins, therapeutic drugs, protein phosphorylation, and G proteins. In addition to providing basic information, the results are expected to contribute to development of new therapeutic drugs and to understanding of brain function.